Changes in the composition of molecular species of covalently bound and free ceramides [EOS], and their correlation with disease severity in atopic dermatitis.

Ceramides are major constituents of stratum corneum (SC) intercellular lipids involved in skin barrier function. The ratio of molecular species of ceramides and their correlation with disease severity was examined in patients with atopic dermatitis (AD). Thirty-eight patients with AD and 32 healthy controls (HCs) were assessed for transepidermal water loss, SC collection and clinical assessment. The ceramide content of different molecular species in the samples was quantified using high-performance liquid chromatography coupled with tandem mass spectrometry. Unsaturated acyl chains of both covalently bound and free ceramides [EOS] were higher in AD lesional skin than those in AD non-lesional or normal HC skin. The proportion of unsaturated acyl chains (C30:1, C32:1 and C34:1) was higher than other ceramide molecular species among covalently bound and free ceramides [EOS] in patients with AD. The proportion of unsaturated acyl chains in covalently bound ceramides was positively correlated with transepidermal water loss (r = 0.600) when considering the total number of non-lesional and lesional skin. Additionally, thymus and activation-regulated chemokine (TARC) showed a positive correlation with unsaturated acyl chains proportion in AD non-lesional (r = 0.676) and lesional (r = 0.503) skin. Our study is the first to show the increase in unsaturated acyl chains of both covalently bound and free ceramides [EOS] in lesional and non-lesional skin in AD for each molecular species. This increase is associated with dryness and impaired barrier function, which correlates with TARC levels, a marker for the degree of type 2 inflammation. We speculate that type 2 inflammation exacerbation leads to abnormal epidermal lipid metabolism in the skin of patients with AD.

Supermicrovascular anastomosis training using chicken wings and colored water.

Plastic surgeons require experience in supermicroscopic vascular anastomosis. Herein, we report a simple, rapid, and cost-effective training method using chicken wings and colored water. The avian ventral metacarpal artery was selected for dissection and anastomosis to mimic supermicrosurgery. Over 14 weeks (one anastomosis per day), the ulnar artery in 100 chicken wings was exposed by dissection, cut proximally, and injected with blue food dye-colored water by an inexperienced surgeon. After ligating the artery branches, it was cut and subjected to end-to-end anastomosis. Next, colored water was injected into the ulnar artery to check for suture sufficiency. The vessel was re-dissected to inspect the lumen and sutures qualitatively. Of the 100 wings, the first and last 20 wings' ventral metacarpal artery dissection, anastomosis times, and leakage frequency were compared. Avian ventral metacarpal artery diameter was recorded, and the cumulative anastomosis time where individual anastomosis times started decreasing was determined. Leakage rates before and after this point were compared. The avian ventral metacarpal artery diameter was 0.7-0.8 mm. The last 20 wings had significantly shorter median dissection times (12:27 vs. 17:45 min), anastomosis times (9:02 vs. 12:29 min), and leakage rates (15% vs. 70%); more even stitching and parallel ligature points; and less vessel layer inversion than the first 20 wings. After a cumulative anastomosis time of 10 h 26 min, individual times sharply decreased, and the leakage rate decreased significantly (58.3% vs. 23.8%). The proposed method significantly improved supermicrosurgical anastomosis. Thus, we believe that this method will help surgeons improve their supermicrosurgical skills.

First clinical evaluation of the QIAreachTM QuantiFERON-TB for tuberculosis infection and active pulmonary disease.

OBJECTIVE: 1) to compare the QIAreachTM QuantiFERON-TB (QIAreach QFT) vs. QuantiFERON®-TB Gold Plus assay (QFT-Plus) to detect tuberculosis (TB) infection; 2) to evaluate diagnostic sensitivity of QIAreach QFT using active TB as surrogate for TB infection; 3) to preliminarily evaluate QIAreach QFT in immunocompromised individuals. METHODS: QIAreach QFT measures the level of interferon-γ (IFN-γ) in plasma specimens from blood stimulated by ESAT-6 and CFP-10 peptides in one blood collection tube (equivalent to the TB2 tube of the QFT-Plus). QIAreach QFT was applied to plasma samples from 41 patients with pulmonary TB and from 42 healthy or low-TB-risk individuals. RESULTS: Sensitivity and specificity of QIAreach QFT vs. QFT-Plus were 100% (41/41) and 97.6% (41/42), respectively; overall concordance was 98.8% (82/83). All samples were measured within 20 min. The time to result of each sample was significantly correlated with IFN-γ level with a natural logarithmic scale (r = -0.913, p < 0.001). Seven cases in the active TB group were immunocompromised (CD4 <200/µL) and tested positive by QIAreach QFT. CONCLUSIONS: QIAreach QFT provides an objective readout with a minimum blood sample volume (1 mL/subject), potentially being a useful point-of-care screening test for TB infection in high-TB-burden, low-resource countries and for immunocompromised patients.

The experiences of foreign-educated nurses in Japan: a systematic review.

AIM: To conduct a systematic review to understand the experiences of foreign-educated nurses in Japan. BACKGROUND: The experiences of foreign nurses in host countries, and the challenges they face, have been widely investigated around the world. However, no systematic review has focused on the experience of foreign-educated nurses in Japan. METHODS: A systematic literature review was conducted by following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines. Japan Medical Abstract Society, Citation Information by National Institute of Informatics, Cumulative Index to Nursing and Allied Health Literature, and PubMed databases were used for the literature search. Inclusion criteria were research articles published between 2013 and 2020 written in Japanese or English. A quality assessment was performed using Version 2018 of the Mixed Methods Appraisal Tool. Selected articles were read repeatedly, and relevant contents were extracted and summarized thematically. RESULTS: Twenty-five studies were selected for the review. The themes generated included (1) reasons for nurses to come to Japan, (2) experiences and current situations among the Economic Partnership Agreement nurses/nurse candidates living in Japan, and (3) experiences and current situation of nurses who had returned to their home countries. The second theme was classified into four categories: language and communication barriers, low pass rates for the national qualification exam, adaptation to workplaces and social environments, and psychological distress. CONCLUSION: Foreign nurses in Japan face various challenges and difficulties, even after they return to their home countries. Solving these problems may improve the wellbeing of foreign-educated nurses in Japan. IMPLICATIONS FOR NURSING POLICY: The results from the current review highlight the necessity for immediate intervention by policymakers to improve the current support system for Economic Partnership Agreement nurses/nurse candidates. A thorough pre-arrival orientation should be provided for the nurse candidates to able them to make a well-informed choice.

Causes of Ineligibility for Recipients in Living Kidney Transplantation.

BACKGROUND: Even if a living donor candidate exists, there are some cases that do not result in kidney transplantation (KTx) due to problems on the recipient side. The aim of this study was to clarify causes of ineligibility for KTx in these cases, so as to make RTx more applicable for patients. METHODS: We targeted 470 patients with end-stage renal disease who applied for the primary kidney KTx from 2010 to 2012. Then we selected those who were not applicable for KTx and investigated recipient causes of ineligibility for KTx or not receiving KTx. RESULTS: The average age of recipients was 47.6 ± 12.9 (7-82) years. A majority of the 470 patients were male (n = 305, 64.9%). Two hundred ninety-seven patients intended to receive a living donor KTx and the others hoped for a deceased donor KTx. Of the 297 patients, 207 (70.0%) underwent KTx and 9 (1.9%) were being prepared for KTx at the time of the survey. Eighty-three patients (27.9%) did not receive a living KTx, with 59 of these due to recipient-related problems and 30 due to donor-related problems. We further classified the reasons for these 59 recipients not undergoing KTx as follows: (1) unclear reasons (35.6%); (2) insufficient intention to receive transplant (13.6%); (3) heart disease (10.2%); (4) malignancy (8.5%); (5) immunologic risks (5.1%); (6) death during the waiting period (5.1%); (7) cerebrovascular events (5.1%); (8) cardiovascular problems (5.1%); (9) psychiatric disorders (3.4%); and (10) infections (3.4%). CONCLUSION: Nearly 50% of the reasons for ineligibility as a recipient were related to their intention to receive KTx, with 94.9% of the nontransplanted cases due to nonimmunologic reasons. Thanks to the recent advances in immunosuppressive therapy, there were only 3 patients who could not undergo KTx due to immunologic risks. Based on these results, transplant surgeons should not only emphasize physical evaluation but should also pay careful attention to the recipient's intention to receive KTx.

Population pharmacokinetics and pharmacodynamics of mycophenolic acid using the prospective data in patients undergoing hematopoietic stem cell transplantation.

Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is used to suppress GvHD in patients undergoing hematopoietic stem cell transplantation (HCT). The purpose of this study was to construct a population pharmacokinetic and pharmacodynamic model in HCT patients for individualized MPA therapy. Blood samples were obtained from 49 HCT patients after starting MMF therapy. Population pharmacokinetic and pharmacodynamic parameters were obtained using the program NONMEM. MPA was described via a one-compartment model with a first-order elimination, and 30.9% of MPA glucuronide (MPAG) was found in the enterohepatic circulation. Inosine-5'-monophosphate dehydrogenase (IMPDH) activity was modeled as a maximal inhibitory model with a half-maximal inhibitory concentration (IC50) of 3.59 µg/mL against MPA concentrations. Simulations based on the obtained pharmacokinetic and pharmacodynamic parameters revealed that decreased creatinine clearance increases the MPAG concentration followed by an increased MPA concentration; therefore, IMPDH activity decreases. Diarrhea decreases the enterohepatic circulation of MPAG and consequently reduces MPA concentration. The IC50 for MPA exhibited a positive association with C-reactive protein. Dosage adjustment based on plasma MPA concentration is required especially for patients with renal dysfunction and/or diarrhea.

Quantitative metabolomics of a xylose-utilizing Saccharomyces cerevisiae strain expressing the Bacteroides thetaiotaomicron xylose isomerase on glucose and xylose.

The yeast Saccharomyces cerevisiae cannot utilize xylose, but the introduction of a xylose isomerase that functions well in yeast will help overcome the limitations of the fungal oxido-reductive pathway. In this study, a diploid S. cerevisiae S288c[2n YMX12] strain was constructed expressing the Bacteroides thetaiotaomicron xylA (XI) and the Scheffersomyces stipitis xyl3 (XK) and the changes in the metabolite pools monitored over time. Cultivation on xylose generally resulted in gradual changes in metabolite pool size over time, whereas more dramatic fluctuations were observed with cultivation on glucose due to the diauxic growth pattern. The low G6P and F1,6P levels observed with cultivation on xylose resulted in the incomplete activation of the Crabtree effect, whereas the high PEP levels is indicative of carbon starvation. The high UDP-D-glucose levels with cultivation on xylose indicated that the carbon was channeled toward biomass production. The adenylate and guanylate energy charges were tightly regulated by the cultures, while the catabolic and anabolic reduction charges fluctuated between metabolic states. This study helped elucidate the metabolite distribution that takes place under Crabtree-positive and Crabtree-negative conditions when cultivating S. cerevisiae on glucose and xylose, respectively.

Influence of Long-term Dialysis on the Outcome of Kidney Transplantation: A Single-Center Study.

AIM: We investigated clinical outcomes of patients in Japan with a history of long-term dialysis treatment. METHODS: We conducted 1171 kidney transplantations between 2000 and 2015. Sixty of the patients had undergone dialysis therapy for >20 years before the transplantation. We compared graft and patient survivals between the recipients with >20 years of dialysis (long dialysis group [LGD]) and those with <20 years (control group [CG]) in a case-control study, in which sex and age of both donors and recipients, ABO compatibility, and calendar year of transplantation were matched. RESULTS: Average age of LDG was 52.8 ± 8.9 years, and that of CG was 54.2 ± 12.6 (P > .05). Durations of dialysis were 25.4 ± 1.57 vs 5.8 ± 5.8 years, respectively (P < .05). The graft survival rates were 91.6%, 89.9%, and 81.8% at 3, 5, and 10 years in LDG vs 90.71%, 84.8%, and 78.3% in CG, respectively (P > .05). The patient survival rates were 96.6%, 93.2%, and 88.6% in LDG vs 94.5%, 91.0%, and 83.9%, respectively (P > .05). There was no significant difference in mean estimated glomerular filtration rates for post-transplant 10 years between them. CONCLUSION: LDG showed satisfying clinical outcomes comparable to those of CG both in graft and patient survivals and renal function.

Hard x-ray photoemission study of Yb1-x Zr x B12: the effects of electron doping on the Kondo insulator YbB12.

We have carried out hard x-ray photoemission spectroscopy (HAXPES) of Yb1-x Zr x B12 ([Formula: see text]) to study the effects of electron doping on the Kondo insulator YbB12. The Yb valences of Yb1-x Zr x B12 at 300 K estimated from the Yb 3d HAXPES spectra decreased after substituting Yb with Zr from 2.93 for YbB12 to 2.83 for Yb0.125Zr0.875B12. A temperature dependent valence decrease was found upon cooling for all doping concentrations. We found peak shifts of the B 1s and Zr 3d5/2, and Yb3+ 4f spectra toward the deeper binding-energy with increasing Zr concentration, which indicates a shift of the Fermi level to the higher energy and that of the Yb 4f hole level close to the Fermi level, respectively, due to electron doping. These results qualitatively show the enhanced hybridization between the Yb 4f and conduction-band states with Zr substitution, consistent with magnetic susceptibility measurements.

Mesenchymal stromal cell infusion to treat steroid-refractory acute GvHD III/IV after hematopoietic stem cell transplantation.

Acute GvHD (aGvHD) is a life-threatening complication of hematopoietic stem cell transplantation. Frontline therapy for aGvHD consists of corticosteroid administration. However, ∼25% of the patients have a steroid-refractory disease, a sign of poor prognosis. An alternative therapy for steroid-refractory aGvHD is infusion of mesenchymal stromal cells (MSCs). Herein, we report the results of 46 patients treated with MSC infusion as salvage therapy for steroid-refractory aGvHD III/IV (78% grade IV). Patients received a median cumulative dose of MSCs of 6.81 × 106/kg (range, 0.98-29.78 × 106/kg) in a median of 3 infusions (range, 1-7). Median time between the onset of aGvHD and the first MSC infusion was 25.5 days (range, 6-153). Of the patients, 50% (23/46) presented clinical improvement. Of these, 3 patients (13%) had complete response, 14 (61%) had partial response and 6 (26%) had transient partial response. The estimated probability of survival at 2s year was 17.4%. Only 2 patients (4.3%) presented acute transient side effects (nausea/vomiting and blurred vision) during cell infusion. No patient had late or severe side effects because of MSC infusion. These results suggest that this therapeutic modality is safe and should be considered for steroid-refractory aGvHD, especially in countries where other second-line agents are less available.

A novel LSD1 inhibitor NCD38 ameliorates MDS-related leukemia with complex karyotype by attenuating leukemia programs via activating super-enhancers.

Lysine-specific demethylase 1 (LSD1) regulates gene expression by affecting histone modifications and is a promising target for acute myeloid leukemia (AML) with specific genetic abnormalities. Novel LSD1 inhibitors, NCD25 and NCD38, inhibited growth of MLL-AF9 leukemia as well as erythroleukemia, megakaryoblastic leukemia and myelodysplastic syndromes (MDSs) overt leukemia cells in the concentration range that normal hematopoiesis was spared. NCD25 and NCD38 invoked the myeloid development programs, hindered the MDS and AML oncogenic programs, and commonly upregulated 62 genes in several leukemia cells. NCD38 elevated H3K27ac level on enhancers of these LSD1 signature genes and newly activated ~500 super-enhancers. Upregulated genes with super-enhancer activation in erythroleukemia cells were enriched in leukocyte differentiation. Eleven genes including GFI1 and ERG, but not CEBPA, were identified as the LSD1 signature with super-enhancer activation. Super-enhancers of these genes were activated prior to induction of the transcripts and myeloid differentiation. Depletion of GFI1 attenuated myeloid differentiation by NCD38. Finally, a single administration of NCD38 causes the in vivo eradication of primary MDS-related leukemia cells with a complex karyotype. Together, NCD38 derepresses super-enhancers of hematopoietic regulators that are silenced abnormally by LSD1, attenuates leukemogenic programs and consequently exerts anti-leukemic effect against MDS-related leukemia with adverse outcome.

Pregnancies with factor V deficiency: a case report and review of the literature.

CASE REPORT: A 30-year-old Japanese nulliparous woman visited for pregnancy at 33 weeks with a massive ovarian tumor located in the pouch of Douglas. By preoperative screening, her prothrombin time (PT) and activated partial thromboplastin time (APTT) were prolonged, and her FV activity was significantly decreased to 4.8%. After prophylactic FFP 20 ml/kg was administered and her FV factor was 19.3%, cesarean delivery was performed, and her perioperative course was uneventful. One year later, she underwent a dilatation and evacuation because of a missed abortion, although prophylactic FFP was not administered. During a third pregnancy, after prophylactic FFP 20 ml/kg was administered and FV activity increased to 21.1%, elective cesarean delivery was performed, and her postoperative course was uneventful. CONCLUSION: For surgical therapy or delivery, the goal of therapy is to maintain FV activity above 20%. It is particularly useful to administer prophylactic FFP.

Principal component analysis uncovers cytomegalovirus-associated NK cell activation in Ph+ leukemia patients treated with dasatinib.

Dasatinib treatment markedly increases the number of large granular lymphocytes (LGLs) in a proportion of Ph+ leukemia patients, which associates with a better prognosis. The lymphocytosis is predominantly observed in cytomegalovirus (CMV)-seropositive patients, yet detectable CMV reactivation exists only in a small fraction of patients. Thus, etiology of the lymphocytosis still remains unclear. Here, we identified NK cells as the dominant LGLs expanding in dasatinib-treated patients, and applied principal component analysis (PCA) to an extensive panel of NK cell markers to explore underlying factors in NK cell activation. PCA displayed phenotypic divergence of NK cells that reflects CMV-associated differentiation and genetic differences, and the divergence was markedly augmented in CMV-seropositive dasatinib-treated patients. Notably, the CMV-associated highly differentiated status of NK cells was already observed at leukemia diagnosis, and was further enhanced after starting dasatinib in virtually all CMV-seropositive patients. Thus, the extensive characterization of NK cells by PCA strongly suggests that CMV is an essential factor in the NK cell activation, which progresses stepwise during leukemia and subsequent dasatinib treatment most likely by subclinical CMV reactivation. This study provides a rationale for the exploitation of CMV-associated NK cell activation for treatment of leukemias.

Kelvin probe imaging of photo-injected electrons in metal oxide nanosheets from metal sulfide quantum dots under remote photochromic coloration.

Metal oxide and quantum dot (QD) heterostructures have attracted considerable recent attention as materials for developing efficient solar cells, photocatalysts, and display devices, thus nanoscale imaging of trapped electrons in these heterostructures provides important insight for developing efficient devices. In the present study, Kelvin probe force microscopy (KPFM) of CdS quantum dot (QD)-grafted Cs4W11O36(2-) nanosheets was performed before and after visible-light irradiation. After visible-light excitation of the CdS QDs, the Cs4W11O36(2-) nanosheet surface exhibited a decreased work function in the vicinity of the junction with CdS QDs, even though the Cs4W11O36(2-) nanosheet did not absorb visible light. X-ray photoelectron spectroscopy revealed that W(5+) species were formed in the nanosheet after visible-light irradiation. These results demonstrated that excited electrons in the CdS QDs were injected and trapped in the Cs4W11O36(2-) nanosheet to form color centers. Further, the CdS QDs and Cs4W11O36(2-) nanosheet composite films exhibited efficient remote photochromic coloration, which was attributed to the quantum nanostructure of the film. Notably, the responsive wavelength of the material is tunable by adjusting the size of QDs, and the decoloration rate is highly efficient, as the required length for trapped electrons to diffuse into the nanosheet surface is very short owing to its nanoscale thickness. The unique properties of this photochromic device make it suitable for display or memory applications. In addition, the methodology described in the present study for nanoscale imaging is expected to aid in the understanding of electron transport and trapping processes in metal oxide and metal chalcogenide heterostructure, which are crucial phenomena in QD-based solar cells and/or photocatalytic water-splitting systems.